Obesity leads to fatty liver disease, impairs glucose and lipid metabolism, and increases the risk of coronary heart disease (CHD). Endogenous sex hormones are important for metabolic health in men and women. However, significant species differences have been an obstacle to defining how endogenous estrogens and androgens impact metabolism and CHD risk with obesity. In older humans, replacement strategies with either hormone lead to dyslipidemia, and often increased CHD risk, a biology not reproduced in mice. One key species difference is that humans express cholesteryl ester transfer protein (CETP), which mice lack. Using mice transgenic for CETP we ?humanized? this pathway, and discovered that CETP is an amplifier of the beneficial glucose-regulating effects of both estrogens and androgens. We discovered that CETP transduces unique and harmful lipid effects of estrogens and androgens, not present without CETP expression, modeling human biology. How CETP directs the liver and adipose tissue to generate these divergent effects is not known. Our overarching hypothesis is that CETP aids fuel partitioning by directing TG to adipose and cholesterol to liver to benefit glucose metabolism with obesity, but activates sex-hormone and sterol signaling pathways that result in dyslipidemia. In this revised proposal we?ve developed tissue-specific approaches to define the liver and adipose mechanisms for CETP?s effects on glucose metabolism, lipid metabolism and atherosclerosis with obesity. We also propose methods to therapeutically modulate these pathways. Efforts at weight loss often fail. The AIMS proposed contribute to a paradigm shift toward activating a ?healthy obesity? pathway. In AIM1 we propose to increase hepatic or adipose CETP tone to re-establish ?healthy obesity? as an alternative to weight loss. In AIM2 we propose to therapeutically modulate the CETP sex-hormone axis to prevent dyslipidemia with sex hormone treatment. We have pilot data that CETP requires delivery of cholesterol through LDL receptor to influence sex hormone action. In AIM3 we will define how the LDL-receptor modulates sex hormone action. In each AIM we will use state-of-the-art tracer methods to simultaneously study glucose and TG flux in vivo so that we may define pathways to create healthy physiology in the setting of nutrient excess. We will assess atherosclerosis at isothermic conditions that accelerate this biology without blocking cholesterol flux. This project focuses on the therapeutic significance of the CETP and LDLR pathways. Our approach is conceptually and technically innovative using novel ?humanized? mouse models and state-of-the-art measurements of nutrient fluxes to establish the basis for clinical studies. These studies address a significant health problem by: 1) Identifying a pathway that contributes to the dramatic CHD protection in premenopausal women. 2) Defining how CETP contributes to the unfavorable effects of sex hormone treatment on dyslipidemia, and translating this into therapeutics. 3) Evaluating novel liver-targeted estrogen treatments to reduce fatty liver. 4) Evaluating how clinically-relevant LDLR-modifying drugs impact metabolic outcomes with estrogen treatment.